Streptococcus pneumoniae is a common invasive mucosal pathogen. Local and systemic manifestations range from asymptomatic colonization, to sinusitis and otitis media, to community-acquired pneumonia, bacteremia, and meningitis, resulting in up to 40,0000 deaths/year in the US alone. The local host and bacterial factors that determine whether S. pneumoniae causes no disease, mucosal disease, or invasive disease are not well-characterized. We propose to characterize the mechanisms of control of pneumococcal infections operative at the initial steps in their pathogenesis from nasopharyngeal colonization to aspiration into upper respiratory mucosae and alveoli, prior to alveolar injury and invasion into tissue and blood. We have shown that IgA reactive with pneumococcal capsular polysaccharide (PPS) mediates killing by neutrophils by both complement-dependent and -independent conditions. IgA and IgG may both contribute to defense of the lower respiratory tract by initiating killing by macrophages and neutrophils and by inhibiting adherence to epithelial cells. We will characterize the molecular and biochemical features of PPS-specific Ig which determine their functional role, their effective interactions with local phagocytic cells, as well as the adaptive mechanisms of the organism which may subvert these protective mechanisms. Hypotheses: (1) Molecular and biochemical characteristics of capsule-specific IgA and IgG (e.g., mutation rates of immunoglobulin genes (VH), momeric, polymeric, and secretory structure of IgA, avidity, and pattern of IgA glycosylation) determine their functional efficiency to inhibit adherence and mediate killing by phagocytes. (2) Bacterial virulence factors (e.g., IgA1 protease, choline-binding protein A, and phase variation) subvert the ability of PPS-specific IgA to control S. pneumoniae. (3) The local host environment (e.g., complement, C-reactive protein) determines the phagocytes' ability of IgA and IgG to initiate killing of S. pneumoniae. The specific objectives of this proposal are designed to illuminate the unique features of the local host-pathogen interaction and defense against these extremely common and serious mucosal infections with S. pneumoniae in children and adults.